Hereditary angioedema (HAE)...Jun 30, 2020 · The international WAO/EAACI guideline for the...

Hereditary angioedema (HAE)

Atsushi Nishizawa

Head of Therapeutic Area Strategy Unit (Rare diseases and Plasma-Derived Therapies)

Takeda Development Center Japan

30 June, 2020

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Today’s Topics

1. What is hereditary angioedema (HAE)?

2. HAE attacks (swelling or pain)

3. Reasons for delay in diagnosis / treatment

4. Global study results of Lanadelumab as prophylaxis treatment

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Today’s Topics





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Mechanism of HAE Attacks⚫ Bradykinin has strong vascular hyperpermeability, and is an important mediator in causing edema in HAE1.

⚫ Bradykinin produced in excess by psychological and physical stress binds to the bradykinin B2 receptor, thereby increasing vascular permeability and causing edema.2-5

C1-INH deficiency or dysfunction in patients with HAE creates an environment conducive to overproduction of attack-inducing bradykinin

When vascular permeability is increased, plasma components in the blood vessels leak from the intravascular space to the extravascular space, causing edema.Attacks usually last for 2 to 5 days

Illustration of Action Mechanisms:Dr. Isao Osawa, the director of Saiyu Soka Hospital

1. Zuraw BL. N Engl J Med. 2008; 359: 1027-362. Craig T, et al. World Allergy Organ J. 2012; 5: 182-993. Tse K, et al. Cleve Clin J Med. 2013; 80: 297-308

When receiving stimulus During HAE attacks

Bradykinin, which is overproduced by stress and other stimuli, binds to the bradykinin B2 receptor, enlarging the gap between vascular endothelial cells and enhancing vascular permeability

4. Shire. FIRAZYR (icatibant) Summary of ProductCharacteristics. June 2017

5. Han ED, et al. J Clin Invest. 2002; 109: 1057-63

Normal

Dermis Lymph vessel Capilliary

Bradykinin B2 receptor

Bradykinin Bradykinin overproduction

Enhanced vascular permeability

5

HAE attacks may appear at multiple sites

Laryngial edema 1,2

• Dysphagia

• Hoarseness

• Voice change

• Shortness of breath

• Suffocation if severe

Photo: Bas, M., et al. 20063

Gastrointestinal edema 1, 4

• Nausea

• Vomiting

• Diarrhoea

• Colic-like pain

Facial edema 1

• Facial and lip swelling• Rarely with laryngeal edema

Rash 6, 7

• Rare non-pruritus rashe.g. related erythema

1 of Skin Edge Edema

• 1 such as redundancy or blistering of the skin

• Swollen 1 of the hands, arms, feet, lower limbs, and femoral region

• Range of motion8

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Characteristics of HAE Attacks

photo：LoCascio et al. 20105

photo： 2016 haeimages.com

photo： Bygum et al. 20097

photo： 2016 haeimages.com

1. Bork, K., et al.：Am. J. Med., 2006, 119 (3), 2672. Bork, K., et al.：J. Allergy. Clin. Immunol., 2012, 130 (3), 6923. Bas, M., et al.：Allergy. 2006, 61 (12), 14904. Bork, K., et al.：Am. J. Gastroenterol., 2006, 101 (3), 619

5. LoCascio, E. J., et al.：West. J. Emerg. Med., 2010, 11 (4), 3916. Magerl, M., et al.：Clin. Exp. Dermatol., 2014, 39 (3), 2987. Bygum, A.：Br. J. Dermatol., 2009, 161 (5),11538. Craig, T., et al.：Ann. Allergy. Asthma. Immunol., 2009, 102 (5), 366

Skin edema of the extremities 1,8

• Redundancy or blistering of the skin

• Swelling of the hands, arms, feet, lower limbs, and femoral region

• Limited range of motion

Symptom of HAE Attacks (1)

Not actual patients. Images showing HAE swelling for educational purpose7

Symptom of HAE Attacks (2)

Not actual patients. Images showing HAE swelling for educational purpose8

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Epidemiology and Clinical Characteristics of HAE Patients

1. The incident rate is 1 out of 50,000 people, with an estimated 2,500 patients in

Japan. The number of patients actually being treated is just over 400.

2. The average number of attacks is 17.9 per year, 55% of which are treated.

3. 27% of patients have more than 20 attacks per year.

4. Length of hospitalization is 9.9 days for each attack before diagnosis and 5.1

days after diagnosis.

5. 60% of patients have difficulty in their daily lives; in particular 29% have

difficulty in attending school, 40% have difficulty traveling, and 41% have limits

on their daily activities.

Hereditary Angioedema (HAE) Guidelines Revised 2014 Version

Bu

rde

n o

f d

ise

ase

Illustrative period in patient lifetime

Attack frequency and/or severity can be triggered by procedures,

minor illness, stressful life events, fatigue, hormonal factors, or

unknown reasons. Triggers tend to be identified during an attack1,2

Severe and life-threatening attacks may occur at any time, even after

long periods of low disease activity. Symptoms include pain, soreness

and fatigue. Attacks initiate an acute treatment process1,2

Between attacks, patients often experience significant anxiety, fear

and isolation that affects their quality of life. Patients often

prepare for future attacks which can facilitate oppression,

depression and low mood3,4

Treatment aims to improve patients’ quality of life toachieve disease control5,6

1. Busse PJ, Christiansen SC. Hereditary Angioedema. N Engl J Med. 2020;382(12):1136‐1148. doi:10.1056/NEJMra18080122. Longhurst HJ, Bork K. Hereditary angioedema: an update on causes, manifestations and treatment. Br J Hosp Med (Lond). 2019;80(7):391‐398. 3. Longhurst H, Bygum A. The Humanistic, Societal, and Pharmaco-economic Burden of Angioedema. Clin Rev Allergy Immunol. 2016;51(2):230‐239. 4. Bygum A, Aygören-Pürsün E, Beusterien K, et al. Burden of Illness in Hereditary Angioedema: A Conceptual Model. Acta Derm Venereol. 2015;95(6):706‐710. 5. Maurer M, Magerl M, Ansotegui I, et al. The international WAO/EAACI guideline for the management of hereditary angioedema-The 2017 revision and update. Allergy. 2018;73(8):1575-1596. 6. Betschel S, Badiou J, Binkley K, et al. The International/Canadian Hereditary Angioedema Guideline [published correction appears in Allergy Asthma Clin Immunol. 2020 May 6;16:33]. Allergy Asthma Clin Immunol. 2019;15:72. Published 2019 Nov 25.

HAE disease activity and impact are variable over time,but all patients may experience severe, life-threatening attacks

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VIDEO

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*Medications include estrogen-containing oral contraceptives, hormone replacement therapies, ACE inhibitors.1,2

HAE, hereditary angioedema; US, United States

1. Lumry WR. Am J Manag Care 2013;19:S103–S110; 2. Farkas H, et al. Allergy 2017;72:300–13;3. Steiner UC, et al. Orphanet J Rare Dis. 2018;13:90; 4. Caballero T, et al. J Invest Allergol Clin Immunol. 2016;26:383–86

Possible triggers for HAE attacks1–4

• Many attacks, particularly among children, occur without a clear trigger

• Common triggers include mechanical trauma, mental stress and airway infection

• Dental eruption is not a common trigger but can provoke an attack in some children

• Menstruation and ovulation are common triggers in adolescent girls

• The same trigger may not always provoke an attack

Airway infection

Certain foods or medications*

Minor trauma

Emotional stress

Hormonal influencesSurgery or

dental procedure

Exposure to cold

HAE attack

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The trigger of an HAE attack is not always necessarily clear, and it is difficult to anticipate and take short-term measures to prevent an attack

Triggers of HAE Attacks

HAE, hereditary angioedema

1. Zuraw BL. N Engl J Med. 2008;359:1027–36; 2. MacGinnitie AJ. Pediatr Allergy Immunol. 2014;25:420–7;3. Banerji A, et al. Ann Allergy Asthma Immunol. 2013;111:329–36

• Symptoms typically worsen over the first 24 hours and subside over the next 48–72 hours

– Attacks can last up to 5 days and may spread to another location before resolving

Course of a typical untreated HAE attack1–3

Trig

ger

even

t(s

om

e ca

ses)

Pro

dro

mal

sy

mp

tom

s(s

om

e ca

ses)

Sym

pto

m o

nse

t

Sym

pto

m in

ten

sity

Hours to days Increasing intensity 12–36 hours

Slow resolution 2–5 days

Time from onset

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Once an attack begins, the symptoms rapidly increase in intensity, and then take time to fully disappear

Clinical Presentation and Course of HAE Attacks

1. “[Among the various HAE attacks], laryngeal swelling has always been my and every HAE patient’s

worst fear... This fear is something that we think about every day and often the last thing that we

think about at night.” Patients speak of the trauma of emergency resuscitation.

2. “When my face swells up, it makes me look like a monster.” Children unable to go to school miss out

on the experience of schoolwork, sports and holidays enjoyed by many ordinary, healthy students.

3. “I missed [almost] 70 days of school due to stomach pains.” Despite taking many different drugs, the

pain was continuous.

4. “I had to quit my job because I could not hold anything. My hands would swell up too much.”

5. “Any time I had an attack, I would lose three to four days out of work… in and out of hospitals.”

“[because of sudden attacks] you would feel that your colleagues could not depend on you.”

“I have lost 14 jobs because of this disease.”

6. “I have no social life…” Anxiety and fatigue are always present, causing depression. “It [HAE] definitely

affects all aspects of your life.”

The Voice of the PatientA series of reports from the U.S. Food and Drug Administration's Patient-Focused Drug Development Initiative "Hereditary Angioedema", May 2018https://www.fda.gov/media/113509/download15

The Voice of the Patient (U.S., 2018)

https://www.fda.gov/media/113509/download

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1) Series from Swollen Abdomen Navi PRO https://www.harefukutsuu-hae.jp/17

⚫ Bradykinin is produced by the decomposition of polymorphic kininogens after activation of factor XII (the contact system) and the

activation of the kallikrein-kinin system. Plasmin also breaks down polymorphic kininogens and produces bradykinin.

⚫ C1-INH suppresses bradykinin production in several steps in these pathways ( = C1-INH point of action).

⚫ Deficiency/dysfunction of C1-INH and excessive function of factor XII all cause HAE by increasing blood levels of bradykinin.

Coagulation Factor XII(Hageman Factor)

Activated Factor XII

vascular endothelial dysfunction/

Exposed collagen

kallikrein-kinin system

coagulation system

fibrinolysis system

prekallikrein

kallikrein

high-molecular-weight kininogenBradykinin

Angioedema


plasminogen

plasmin

Inactivatingpeptide

ACE inhibitor

Kininase II(ACE)

Activate

Produce or Activating

C1-INH point of action(inhibitory action)

Involvement of C1-INH in Angioedema

1) Series from Swollen Abdomen Navi PRO https://www.harefukutsuu-hae.jp/18

Coagulation Factor XII(Hageman Factor)

Activated Factor XII

vascular endothelial dysfunction/

Exposed collagen

kallikrein-kinin system

coagulation system

fibrinolysis system

prekallikrein

kallikrein

high-molecular-weight kininogenBradykinin

Angioedema


plasminogen

plasmin

Inactivatingpeptide

ACE inhibitor

Kininase II(ACE)

Activate

Produce or Activating

C1-INH point of action(inhibitory action)

When C1-INH ceases to function…

⚫ Bradykinin is produced by the decomposition of polymorphic kininogens after activation of factor XII (the contact system) and the

activation of the kallikrein-kinin system. Plasmin also breaks down polymorphic kininogens and produces bradykinin.

⚫ C1-INH suppresses bradykinin production in several steps in these pathways ( = C1-INH point of action).

⚫ Deficiency/dysfunction of C1-INH and excessive function of factor XII all cause HAE by increasing blood levels of bradykinin.

Several types of HAE have been identified:

Type I• Low plasma levels of C1-INH protein1–5

• Bradykinin mediated (contact system)5

Type II• Normal plasma levels of C1-INH protein1–5

• Dysfunctional C1-INH protein1–5

• Bradykinin mediated (contact system)5

HAE due to C1-INH deficiency or dysfunction3,6

HAE with normal C1-INH levels and function3,6

85%*1,3,5

15%*1,3,5

Very few1,3

HAE

*In Chinese patients, Type I and Type II HAE account for 98.7% and 1.3% of cases, respectively.7 †Previously referred to as ‘Type III’.3,6

C1-INH, C1 esterase inhibitor; HAE, hereditary angioedema; HAE-ANGPT1, HAE with an angiopoietin-1 gene mutation; HAE-FXII, HAE with a known Factor XII gene mutation; HAE-PLG, HAE with a mutation in the plasminogen gene.1. Lumry WR. Am J Manag Care 2013;19:S103–S110; 2. Zuraw BL. J Allergy Clin Immunol 2018;14:884–845; 3. Zuraw BL. N Engl J Med 2008;359:1027–1036; 4. Cicardi M et al. Allergy 2014;69:602–616; 5. Longhurst HJ & Bork K. Br J Hosp Med 2019;80:391–398; 6. Bafunno V et al. J Allergy Clin Immunol 2018;141:1009–1017; 7. Zhi Y et al. Eur J Dermatol 2019;29:14–20.

HAE with normal C1-INH†

• HAE-FXII5; bradykinin mediated (contact system)5

• HAE-ANGPT15,7; bradykinin mediated (vascular system)5

• HAE-PLG5; bradykinin mediated (fibrinolytic system)5

• HAE-unknown5; presumed bradykinin mediated5

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Classification of HAE disease type

• Abdominal pain• Appendicitis• Biliary disorders• Colitis• Diverticulitis• Endometriosis

• Airway obstruction• Allergy (incl. anaphylaxis)• Asthma• GERD• Infections of upper airways• Other forms of angioedema

• Gastroenteritis• Irritable colon• Kidney problems• Pancreatitis• Peptic ulcer/GERD

• Cutaneous/mucosal swelling• Allergy• Cutaneous disorders• Urticaria• Other forms of angioedema

In most of these

conditions symptoms are

often recurrentand combined

Disorders are examples of diagnoses reported by HAE patients with other conditions misdiagnosed prior to HAE diagnosis or conditions to be considered for differential diagnosis of HAE. Agostoni A et al. J Allergy Clin Immunol 2004; Bork K et al. Am J Med 2006; Farkas H. Allergy Asthma Clin Immunol 2010;Papadopoulou-Alataki E. Curr Opin Allergy Clin Immunol 2010; Ali MA et al. Clin Exp Gastroenterol 2014; Zanichelli A et al. Ann Allergy Asthma Immunol 2016.

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Diagnosis of HAE is not exclusive,but should be considered as an option in differential diagnosis

Signs & symptoms of HAE are not specific andoften lead to misdiagnoses

Importance of HAE Diagnosis for Reducing Mortalityfrom Laryngeal Attacks*

*Note: The information on this slide is from one study, which had a partly retrospective and partly prospective design and analyzed a total of 728 patients from 182 families with HAE-C1-INH.At the time of evaluation (October 2011), 214 patients had died.HAE, hereditary angioedema; HAE-C1-INH, hereditary angioedema due to C1 inhibitor deficiencyBork K, et al. J Allergy Clin Immunol. 2012;130:692–7

29%

3%vs

Mortality due to asphyxiation from laryngeal attacksin patients undiagnosed with HAE (n=63/214)

Mortality due to asphyxiation from laryngeal attacksin patients diagnosed with HAE (n=7/214)

• Lifespan of undiagnosed patients with HAE who die from laryngeal

attacks is an average 31 years shorter than undiagnosed patients

who die from other causes

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Diagnosis has significant impact on mortality rates

Diagnosis of Hereditary Angioedema is often delayed

50

40

30

20

10

0

Co

un

t

60

Age (years)

2 4 6 8 10 12 14 16 18 20

Age at onset of first swelling(mean = 11 years)

120

100

80

60

40

20

010 20 30 40 50 60 70

Co

un

t

Age (years)

Age at diagnosis(mean = 19 years)

HAE, hereditary angioedema.Retrospective study in 581 US patients with HAE. Christiansen SC et al. Clin Pediatr 2016.22

Median delay in diagnosis = 8 years (range 0-55)

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Today’s Topics





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Mechanism of Action of Lanadelumab

Lanadelumab

The HELP Study: A Randomized, Double-blind, Placebo-controlled, Parallel-arm, Multicenter Phase 3 Study1–5

*LTP washout only for patients ≥18 years of age; †Run-in period could be shortened if patient experienced ≥3 attacks before completion of 4 weeks, and period could be extended to 8 weeks if patient did not experience any attacks during 4 weeks; ‡To assess the efficacy and safety of lanadelumab by baseline attack frequency relative to placebo, randomization was stratified by baseline attack rate (1 to <2, 2 to <3, or ≥3 attacks/month [defined as a 4-week period or 28 days])3; §Treatments administered as 2 separate 1 mL injections in the upper arm every 2 weeks to maintain the blind.C1-INH = C1 esterase inhibitor; C1-INH-HAE = HAE with C1-INH deficiency; HELP = Hereditary angioEdema Long-term Prophylaxis; LTP = long-term prophylaxis; q2wks = every 2 weeks; q4wks = every 4 weeks 1. Clinicaltrials.gov [NCT02586805]. Accessed April 2018; 2. Banerji A, et al. Presented at the American College of Allergy, Asthma and Immunology (ACAAI) 74th Annual Scientific Meeting, October 26–30, 2017, Boston, MA; 3. Riedl MA, et al. Presented at the 2018 American Academy of Allergy, Asthma and Immunology (AAAAI)/World Allergy Organization (WAO) Joint Congress, March 2–5, 2018, Orlando, FL; Poster #151; 4. Johnston DT, et al. Presented at the American College of Allergy, Asthma and Immunology (ACAAI) Annual Scientific Meeting, November 15–19, 2018, Seattle, WA; Poster P166; 5. ZurawBL, et al. Presented at the American College of Allergy, Asthma and Immunology (ACAAI) Annual Scientific Meeting, November 15–19, 2018, Seattle, WA; Poster P170

Objective: Investigate the efficacy and safety of lanadelumab for long-term prophylaxis (LTP) against HAE attacks in patients with HAE with C1-INH deficiency (C1-INH-HAE)

≥2 weeks for LTP washout*

4 weeks†‡

26 weeks treatment§

Open-label extension study or

8-week follow-up periodLanadelumab 150 mg (1 mL) q4wks

Lanadelumab 300 mg (2 mL) q4wks

Lanadelumab 300 mg (2 mL) q2wks

Placebo

Run-inScreening

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Primary Endpoint: Lanadelumab Significantly Reduced Mean Attack Rates

Attack rates are presented as /4 weeks (95% CI). Results are from a Poisson regression model; treatment group and normalized baseline attack rate were fixed effects and the logarithm of time (days) each patient was observed during the treatment period wa san offset variable. Adjusted P-values are shown.q4wks = every 4 weeks; q2wks = every 2 weeksBanerji A, et al. Presented at the American College of Allergy, Asthma and Immunology Annual 74th Annual Scientific Meeting, October 26–30, 2017, Boston, MA

0.48

0.26

P<0.001 P<0.001 P<0.001

–75.6%(–84.7, –61.2)

–73.3%(–82.4, –59.5)

–86.9%(–92.8, –76.2)

Placebo,N=41

150 mg q4wks,N=28

300 mg q4wks,N=29

300 mg q2wks,N=27

0.0

0.5

1.0

1.5

2.0

2.5

Me

an a

ttac

k ra

te (

atta

cks/

4 w

ee

ks)

Lanadelumab

1.97

0.53

26

At Steady State (Days 70–182), Lanadelumab Significantly Reduced Mean Attack Rates1,2

Attack rates are presented as attacks/4 weeks and are adjusted for baseline attack severity. Results are from a Poisson regression model. Percentages are reduction in attack rate vs placebo (CI). P-values are not adjusted for multiplicity; *post hoc sensitivity analysis.HAE = hereditary angioedema; LS = least squares; CI = confidence interval; q2wks = every 2 weeks; q4wks = every 4 weeks1. Maurer M, et al. Presented at the 2018 European Academy of Allergy and Clinical Immunology (EAACI) Congress, 26–30 May 2018, Munich, Germany; Poster #0525;2. Shire Data on File: SHP643-002

Exploratory Endpoint*

1.88

0.42 0.370.16

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

Placebon=37

150 mgq4wksn=28

300 mgq4wksn=29

300 mgq2wksn=26

LS m

ean

HA

E at

tack

rat

e, a

ttac

ks/m

on

th–77.6%

(–86.7, –62.3)P<0.001

–80.6%(–88.5, –67.3)

P<0.001

–91.5%(–96.1, –81.1)

P<0.001

Lanadelumab

27

At steady state (Days 70–182), LS mean monthly HAE attack rate was significantly reducedin all lanadelumab treatment arms vs the placebo arm

HAE Attack Rate During Days 0–69 of Treatment and During Steady State

*Attack rates were based on attacks occurring within 2 weeks before each time point. A month was defined as 28 days. Error bars indicate the standard error of the mean.†Attack rates were based on attacks occurring within 4 weeks before each time point. A month was defined as 28 days. Error bars indicate the standard error of the mean.HAE = hereditary angioedema; q2wks = every 2 weeks; q4wks = every 4 weeksMaurer M, et al. Presented at the European Academy of Allergy and Clinical Immunology (EAACI) Congress, June 1–5, 2019, Lisbon, Portugal; Poster PD0369

HAE attack rate during days 0–69 of treatment* HAE attack rate during the steady state period†

Placebo Lanadelumab 150 mg q4wks Lanadelumab 300 mg q4wks Lanadelumab 300 mg q2wks

Att

ack

rate

, att

acks

/mo

nth

0

1

2

3

4

5

Run-in Week 2 Week 4 Week 6 Week 8 Week 10

Study week

Att

ack

rate

, att

acks

/mo

nth

0

1

2

3

4

5

Week 14

Study week

Week 18 Week 22 Week 26

Ad hoc analysis

28

Efficacy with lanadelumab was observed within the first 2 weeks of treatment and was maintained over time

At Steady State (Days 70–182), Even More Lanadelumab-treated Patients were Attack-free and Fewer Experienced a Moderate or Severe Attack1,2

Analysis of maximum attack severity; *post hoc sensitivity analysis.q4wks = every 4 weeks; q2wks = every 2 weeks1. Maurer M, et al. Presented at the 2018 European Academy of Allergy and Clinical Immunology (EAACI) Congress, 26–30 May 2018, Munich, Germany; Poster #0525; 2. Shire Data on File: SHP643-002

Exploratory Endpoint*

Lanadelumab

2.7

27.0

64.9

32.1

53.6

10.7

6.9

34.5

13.8

44.8

3.8

76.9

Placebo,N=37

150 mg q4wks,N=28

300 mg q4wks,N=29

300 mg q2wks,N=26

Pat

ien

ts (

%)

7.7

11.53.6 3.8

Pat

ien

ts (

%)

0

20

40

60

80

100

5.4

No attack

Mild

Moderate

Severe

29

At steady state 76.9% of patients receiving lanadelumab 300 mg q2wks were attack-free compared with 2.7% of placebo-recipients

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Safety: Overview of Adverse Events

Placebo,N=41n (%)

Lanadelumab

150 mg q4wks,N=28n (%)

300 mg q4wks,N=29n (%)

300 mg q2wks,N=27n (%)

Total,N=84n (%)

Any AE 31 (75.6) 25 (89.3) 25 (86.2) 26 (96.3) 76 (90.5)

Any treatment-related AE* 14 (34.1) 17 (60.7) 14 (48.3) 19 (70.4) 50 (59.5)

Any serious AE 0 (0.0) 0 (0.0) 3 (10.3) 1 (3.7) 4 (4.8)

Any related serious AE 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Deaths due to AE 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Discontinuation due to AE 1 (2.4)† 0 (0.0) 1 (3.4) 0 (0.0) 1 (1.2)

There were no deaths or treatment-related serious AEsThere were no deaths or treatment-related serious AEs

*Adverse events that were judged by the investigator to be related to the use of the investigational product.†One patient withdrew due to a HAE attack and is not included.AEs were collected over the entire treatment period and were assigned to the treatment group, irrespective of type of injection (i.e., placebo or active drug in the 150 mg q4wks and 300 mg q4wks groups).AE = adverse event; HAE = hereditary angioedema; q2wks = every 2 weeks; q4wks = every 4 weeksBanerji A, et al. JAMA 2018;320:2108–21

Safety: Adverse Events Reported in ≥5% of Lanadelumab-treated Patients

Treatment-emergent adverse events that were reported at the Preferred Term level in ≥5% of patients in the total lanadelumab-treated group and excludes HAE attack events.AE = adverse event; HAE = hereditary angioedema; q2wks = every 2 weeks; q4wks = every 4 weeksBanerji A, et al. JAMA 2018;320:2108–21

Placebo,N=41 n (%)

Lanadelumab

150 mg q4wks,N=28n (%)

300 mg q4wks,N=29n (%)

300 mg q2wks,N=27n (%)

Total,N=84n (%)

Any AE 31 (75.6) 25 (89.3) 25 (86.2) 26 (96.3) 76 (90.5)

Injection site pain 12 (29.3) 13 (46.4) 9 (31.0) 14 (51.9) 36 (42.9)

Viral upper respiratory tract infection 11 (26.8) 3 (10.7) 7 (24.1) 10 (37.0) 20 (23.8)

Headache 8 (19.5) 3 (10.7) 5 (17.2) 9 (33.3) 17 (20.2)

Injection site erythema 1 (2.4) 4 (14.3) 2 (6.9) 2 (7.4) 8 (9.5)

Injection site bruising 0 (0.0) 3 (10.7) 2 (6.9) 1 (3.7) 6 (7.1)

Dizziness 0 (0.0) 1 (3.6) 3 (10.3) 1 (3.7) 5 (6.0)

The most common AEs were local injection site reactions, viral upper respiratory tract infection, headache, and dizziness

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Safety: Treatment-related Adverse Events Reported in ≥5% of Lanadelumab-treated Patients

*Adverse events that were judged by the investigator to be related to the use of the investigational product.Includes adverse events that were reported at the Preferred Term level in ≥5% of patients in the total lanadelumab-treated group and excludes HAE attack events.AE = adverse event; HAE = hereditary angioedema; q2wks = every 2 weeks; q4wks = every 4 weeksBanerji A, et al. JAMA 2018;320:2108–21

Placebo,N=41n (%)

Lanadelumab

150 mg q4wks,N=28n (%)

300 mg q4wks,N=29n (%)

300 mg q2wks,N=27n (%)

Total,N=84n (%)

Any treatment-related AE* 14 (34.1) 17 (60.7) 14 (48.3) 19 (70.4) 50 (59.5)

Injection site pain 11 (26.8) 12 (42.9) 9 (31.0) 14 (51.9) 35 (41.7)

Injection site erythema 1 (2.4) 4 (14.3) 2 (6.9) 2 (7.4) 8 (9.5)

Injection site bruising 0 (0.0) 2 (7.1) 2 (6.9) 1 (3.7) 5 (6.0)

Headache 1 (2.4) 1 (3.6) 2 (6.9) 3 (11.1) 6 (7.1)

The most common treatment-related AEs were injection site reactions and headache

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Safety: Serious Adverse Events*

*These data are reported in the Supplementary Online Content.q2wks = every 2 weeks; q4wks = every 4 weeks; SAE = serious adverse eventBanerji A, et al. JAMA 2018;320:2108–21

Preferred term

Placebo,N=41n (%)

Lanadelumab

150 mg q4wks, N=28n (%)

300 mg q4wks,N=29n (%)

300 mg q2wks,N=27n (%)

Any SAE 0 (0.0) 0 (0.0) 3 (10.3) 1 (3.7)

Catheter site infection 0 (0.0) 0 (0.0) 0 (0.0) 1 (3.7)

Pyelonephritis 0 (0.0) 0 (0.0) 1 (3.4) 0 (0.0)

Meniscus injury 0 (0.0) 0 (0.0) 1 (3.4) 0 (0.0)

Bipolar II disorder 0 (0.0) 0 (0.0) 1 (3.4) 0 (0.0)

Four SAEs were reported during the study, but none was considered to be related to treatment

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Safety: Adverse Events of Special Interest

• A total of 8 AESIs were reported in 5 patients, all treated with lanadelumab:1

– 2 events of injection site induration in 1 patient receiving lanadelumab 150 mg q4wks

– 2 events of injection site erythema in 1 patient receiving lanadelumab 300 mg q4wks

– 4 events in 3 patients receiving lanadelumab 300 mg q2wks:

• 2 related hypersensitivity events in 1 patient, 1 mild and 1 moderate in severity

– Symptoms of pruritus, itching, and tingling of the tongue were reported for both events; the events resolved within 1 day without interruption of lanadelumab treatment and the patient continued in the study without further reactions

• 1 event of injection site reaction in 1 patient

• 1 mild event of microcytic anemia in 1 patient that was not considered related to treatment

AESIs = adverse events of special interest; q2wks = every 2 weeks; q4wks = every 4 weeks1. Johnston DT, et al. Presented at the American College of Allergy, Asthma and Immunology (ACAAI) Annual Scientific Meeting, November 15–19, 2018, Seattle, WA; Poster P166; 2. Clinical Study Report: DX-2930-03, Shire, September 2017; pp. 2491, 2492, 2519, 2521, 2524, 2527

None led to treatment discontinuation2

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undiagnosed

Elevate prophylaxis standard of care

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Hereditary angioedema (HAE)...Jun 30, 2020 · The international WAO/EAACI guideline for the...

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